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Chemical Reviews Mar 2022Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of... (Review)
Review
Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of hydrogen by deuterium gives rise to improved absorption, distribution, metabolism, and excretion (ADME) properties in drugs and enables the preparation of internal standards for analytical mass spectrometry, the use of tritium-labeled compounds is a key technique all along drug discovery and development in the pharmaceutical industry. For these reasons, the interest in new methodologies for the isotopic enrichment of organic molecules and the extent of their applications are equally rising. In this regard, this Review intends to comprehensively discuss the new developments in this area over the last years (2017-2021). Notably, besides the fundamental hydrogen isotope exchange (HIE) reactions and the use of isotopically labeled analogues of common organic reagents, a plethora of reductive and dehalogenative deuteration techniques and other transformations with isotope incorporation are emerging and are now part of the labeling toolkit.
Topics: Deuterium; Hydrogen; Isotope Labeling; Mass Spectrometry; Tritium
PubMed: 35179363
DOI: 10.1021/acs.chemrev.1c00795 -
Methods in Molecular Biology (Clifton,... 2019Neutron scattering has significant benefits for examining the structure of protein-lipid complexes. Cold (slow) neutrons are nondamaging and predominantly interact with... (Review)
Review
Neutron scattering has significant benefits for examining the structure of protein-lipid complexes. Cold (slow) neutrons are nondamaging and predominantly interact with the atomic nucleus, meaning that neutron beams can penetrate deeply into samples, which allows for flexibility in the design of samples studied. Most importantly, there is a strong difference in neutron scattering length (i.e., scattering power) between protium ([Formula: see text], 99.98% natural abundance) and deuterium ([Formula: see text] or D, 0.015%). Through the mixing of HO and DO in the samples and in some cases the deuterium labeling of the biomolecules, components within a complex can be hidden or enhanced in the scattering signal. This enables both the overall structure and the relative distribution of components within a complex to be resolved. Lipid-protein complexes are most commonly studied using neutron reflectometry (NR) and small angle neutron scattering (SANS). In this review the methodologies to produce and examine a variety of model biological membrane systems using SANS and NR are detailed. These systems include supported lipid bilayers derived from vesicle dispersions or Langmuir-Blodgett deposition, tethered bilayer systems, membrane protein-lipid complexes and polymer wrapped lipid nanodiscs. The three key stages of any SANS/NR study on model membrane systems-sample preparation, data collection, and analysis-are described together with some background on the techniques themselves.
Topics: Deuterium; Humans; Lipid Bilayers; Lipids; Neutron Diffraction; Neutrons; Proteins
PubMed: 31218621
DOI: 10.1007/978-1-4939-9512-7_11 -
Angewandte Chemie (International Ed. in... Feb 2018Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct... (Review)
Review
Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium ( H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.
Topics: Deuterium; Enzymes; Isotope Labeling; Kinetics; Metabolomics; Pharmaceutical Preparations; Proteomics; Tritium
PubMed: 28815899
DOI: 10.1002/anie.201704146 -
Nature Chemistry Mar 2022Isotope labelling, particularly deuteration, is an important tool for the development of new drugs, specifically for identification and quantification of metabolites....
Isotope labelling, particularly deuteration, is an important tool for the development of new drugs, specifically for identification and quantification of metabolites. For this purpose, many efficient methodologies have been developed that allow for the small-scale synthesis of selectively deuterated compounds. Due to the development of deuterated compounds as active drug ingredients, there is a growing interest in scalable methods for deuteration. The development of methodologies for large-scale deuterium labelling in industrial settings requires technologies that are reliable, robust and scalable. Here we show that a nanostructured iron catalyst, prepared by combining cellulose with abundant iron salts, permits the selective deuteration of (hetero)arenes including anilines, phenols, indoles and other heterocycles, using inexpensive DO under hydrogen pressure. This methodology represents an easily scalable deuteration (demonstrated by the synthesis of deuterium-containing products on the kilogram scale) and the air- and water-stable catalyst enables efficient labelling in a straightforward manner with high quality control.
Topics: Catalysis; Deuterium; Hydrogen
PubMed: 35027706
DOI: 10.1038/s41557-021-00846-4 -
Isotopes in Environmental and Health... Aug 2017The main aim goal of this review was to gather information about recent publications related to deuterium oxide (DO), and its use as a scientific tool related to human... (Review)
Review
The main aim goal of this review was to gather information about recent publications related to deuterium oxide (DO), and its use as a scientific tool related to human health. Searches were made in electronic databases Pubmed, Scielo, Lilacs, Medline and Cochrane. Moreover, the following patent databases were consulted: EPO (Espacenet patent search), USPTO (United States Patent and Trademark Office) and Google Patents, which cover researches worldwide related to innovations using DO.
Topics: Biomedical Research; Biotechnology; Deuterium Oxide; Humans
PubMed: 28165769
DOI: 10.1080/10256016.2017.1281806 -
Current Medicinal Chemistry 2023Many drugs have adverse absorption, distribution, metabolism, and excretory (ADME) properties that prevent their widespread use or limit their use in some indications....
Many drugs have adverse absorption, distribution, metabolism, and excretory (ADME) properties that prevent their widespread use or limit their use in some indications. In addition to preparation techniques and prodrug strategies, deuterium modification is a viable method for improving ADME properties. Deuterated drugs have attracted increasing attention from the pharmaceutical industry in recent years. To date, two deuterated drugs have been approved by the FDA. In 2017, austedo was approved by the FDA as a new drug for Huntington's disease in the United States, the first deuterium drug to be marketed worldwide. Recently (June 9, 2021), donafinil has been listed in China; this result has caused major pharmaceutical companies and the pharmaceutical industry to pay attention to deuterium technology again. In addition, BMS-986165, RT001, ALK-001, HC-1119, AVP-786 and other drugs are in phase III clinical studies, and some solid deuterium compounds have entered phase I and II clinical trials. The deuterium strategy has been widely used in pharmaceutical research and has become a hot spot in pharmaceutical research in recent years. In this paper, the research and development of deuterated drugs are reviewed, and the influence of deuterium modification on drugs, the advantages of deuterium strategies and the synthesis strategies of deuterated drugs are mainly introduced. Hoping to provide references for clinical application, the discovery of new deuterium chemical entities and research and development of new deuterated drugs.
Topics: Humans; United States; Deuterium; Huntington Disease; China
PubMed: 36415097
DOI: 10.2174/0929867330666221122123201 -
Biotechnology Advances 2018Stable isotopes are used in wide fields of application from natural tracers in biology, geology and archeology through studies of metabolic fluxes to their application... (Review)
Review
Stable isotopes are used in wide fields of application from natural tracers in biology, geology and archeology through studies of metabolic fluxes to their application as tracers in quantitative proteomics and structural biology. We review the use of stable isotopes of biogenic elements (H, C, N, O, S, Mg, Se) with the emphasis on hydrogen and its heavy isotope deuterium. We will discuss the limitations of enriching various compounds in stable isotopes when produced in living organisms. Finally, we overview methods for measuring stable isotopes, focusing on methods for detection in single cells in situ and their exploitation in modern biotechnologies.
Topics: Animals; Biotechnology; Chlorophyta; Deuterium; Drug Design; Isotope Labeling; Isotopes; Magnetic Resonance Spectroscopy; Mammals; Mass Spectrometry; Plants; Spectrum Analysis, Raman
PubMed: 29355599
DOI: 10.1016/j.biotechadv.2018.01.010 -
Methods in Enzymology 2015Soon after the discovery of deuterium, efforts to utilize this stable isotope of hydrogen for labeling of plants began and have proven successful for natural abundance... (Review)
Review
Soon after the discovery of deuterium, efforts to utilize this stable isotope of hydrogen for labeling of plants began and have proven successful for natural abundance to 20% enrichment. However, isotopic labeling with deuterium ((2)H) in higher plants at the level of 40% and higher is complicated by both physiological responses, particularly water exchange through transpiration, and inhibitory effects of D2O on germination, rooting, and growth. The highest incorporation of 40-50% had been reported for photoheterotrophic cultivation of the duckweed Lemna. Higher substitution is desirable for certain applications using neutron scattering and nuclear magnetic resonance (NMR) techniques. (1)H(2)H NMR and mass spectroscopy are standard methods frequently used for determination of location and amount of deuterium substitution. The changes in infrared (IR) absorption observed for H to D substitution in hydroxyl and alkyl groups provide rapid initial evaluation of incorporation. Short-term experiments with cold-tolerant annual grasses can be carried out in enclosed growth containers to evaluate incorporation. Growth in individual chambers under continuous air perfusion with dried sterile-filtered air enables long-term cultivation of multiple plants at different D2O concentrations. Vegetative propagation from cuttings extends capabilities to species with low germination rates. Cultivation in 50% D2O of annual ryegrass and switchgrass following establishment of roots by growth in H2O produces samples with normal morphology and 30-40% deuterium incorporation in the biomass. Winter grain rye (Secale cereale) was found to efficiently incorporate deuterium by photosynthetic fixation from 50% D2O but did not incorporate deuterated phenylalanine-d8 from the growth medium.
Topics: Biomass; Deuterium; Isotope Labeling; Plant Development; Poaceae
PubMed: 26577734
DOI: 10.1016/bs.mie.2015.07.014 -
Journal of Labelled Compounds &... Nov 2014Deuterium-labelled indatraline was synthesized in high efficiency employing a Friedel-Crafts alkylation of [(2)H6]benzene with (E)-3-(3,4-dichlorophenyl)acrylic acid as...
Deuterium-labelled indatraline was synthesized in high efficiency employing a Friedel-Crafts alkylation of [(2)H6]benzene with (E)-3-(3,4-dichlorophenyl)acrylic acid as a key step. The desired labelling of the final compound was ascertained in two ways, by incorporation of [(2)H6]benzene in the target molecule and additionally by deuterium transfer to the non-deuterated aryl moiety of the Friedel-Crafts alkylation product from [(2)H6]benzene, the latter thus serving as reagent and solvent.
Topics: Deuterium; Indans; Methylamines; Radiopharmaceuticals
PubMed: 25382822
DOI: 10.1002/jlcr.3245 -
Bioorganic Chemistry Jun 2023In organic chemistry, the use of deuterium exchange as a tool to study the mechanism of chemical reaction has been well explored. Since two decades, the research focus... (Review)
Review
In organic chemistry, the use of deuterium exchange as a tool to study the mechanism of chemical reaction has been well explored. Since two decades, the research focus on deuterated bioactive molecules has been gaining attention for investigating the therapeutic potential of deuterium replacement in a chemical structure. Recently, Food Drug Administration (FDA) approved the first deuterium-labeled drug "deutetrabenazine", and notified the deuterated drugs as new chemical entities (NCEs). Henceforth, the deuterium substitution driven structure activity relationship, preclinical pharmacokinetics, and toxicity studies were much initiated. Deuteration of a bioactive molecule often results in improved therapeutic efficacy due to the altered pharmacokinetic profile. This review provides a conceptual framework on the importance of deuterium atom in chemical structure of a drug, and its biological value in improved physiochemical properties, pharmacokinetics, biological target interaction, diagnosis, and toxicity. In addition, this review concisely updated the recent deuteration methods, chemical stability, challenges in drug development, deuterium-based imaging in diagnosis, and selected synthetic scheme of deuterated molecules.
Topics: Deuterium; Drug Development; Pharmaceutical Preparations; Structure-Activity Relationship
PubMed: 37001472
DOI: 10.1016/j.bioorg.2023.106490